Hydrophosphonylation of α-haloalkenals

Article abstract of DOI:10.1002/hc.21081

Polyfunctional β-haloalkenyl α-hydroxy phosphonates were synthesized chemoselectively by an economical alkali metal alkoxide catalyzed reaction of dialkyl phosphites with α-haloenals.

Full text of DOI:10.1002/hc.21081

Heteroatom Chemistry
Volume 00, Number 0, 2013
Hydrophosphonylation of α-Haloalkenals
A. Yu. Rulev
A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033, Irkutsk, Russian Federation
Received 17 August 2012; revised 28 January 2013
and enals, the organophosphorus chemistry of their
ABSTRACT: Polyfunctional β-haloalkenyl α-hydroxy
α-substituted isomers is still terra incognita and
sometimes filled with unusual transformations.
Thus, captodative formyl(amino)alkenes [11] react
phosphonates were synthesized chemoselectively by an
economical alkali metal alkoxide catalyzed reaction
ꢀC
of dialkyl phosphites with α-haloenals.
2013 Wi-
with dialkyl phosphites under classical conditions
giving surprisingly tertiary α-aminoesters [12, 13].
Owing to the intensive development of the chem-
istry and biology of α-hydroxy phosphonates over
the past years, the study of the effect of other het-
eroatom in such a type of compounds in their reac-
tion with the same nucleophiles is of great interest.
In this paper, the chemoselective synthesis of un-
saturated β-halogen α-hydroxy phosphonates from
conjugated α-haloalkenals and dialkyl phosphites is
described.
ley Periodicals, Inc. Heteroatom Chem 00:1–4, 2013;
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hc.21081
INTRODUCTION
α-Hydroxy phosphonates are an important class
of compounds and attract much attention due to
their wide applications in modern pharmaceutical,
agricultural, synthetic, and coordination chemistry
[1–4]. Hydrophosphonylation of aldehydes provides
a highly valuable and direct route for their prepa-
ration. Although a number of examples of the re-
action of α,β-unsaturated carbonyl derivatives with
dialkyl phosphites have been documented, the syn-
thesis of functionalized α-hydroxy phosphonates is
not always an easy task. In general, electron-deficient
alkenes can undergo a 1,2- or 1,4-addition of di-
alkyl phosphites depending of the nature of acti-
vated function and experimental conditions [5–8].
Furthermore, the presence of a good leaving group
is able to promote its substitution by soft phos-
phorus nucleophiles. For example, the treatment of
β-alkoxy- or β-haloenones with dialkyl phosphites
under basic conditions leads to the corresponding
vinyl phosphonates in good yield [9, 10]. In con-
trast to the widely studied β-functionalized enones
RESULTS AND DISCUSSION
Some possible results of the treatment of α-
haloenals with dialkyl phosphites should be ex-
pected. First, as a bifunctional electrophile, α-halo-
α,β-unsaturated aldehydes 1 can react in the 1,2- or
1,4-addition mode to give α-hydroxy phosphonate
or β-ketophosphonates, respectively [5–8]. Second,
like formyl(amino)alkenes [12, 13], they could un-
dergo domino-transformations to form finally sat-
urated α-haloesters. Third, similar to nitrogen nu-
cleophiles, the dialkyl phosphites could participate
in the halogen substitution reaction via the 1,4-
addition–nucleophilic substitution–elimination se-
quence [14]. Eventually, the polymerization of the
formed unsaturated α-hydroxy phosphonates or ini-
tial α-haloenals under the experimental conditions
can be faster than the addition reaction itself. In fact,
it is known that the alkali metal alkoxides initiate the
polymerization of the α-haloenals [15, 16]. So, what
kind of transformations will be realized in this case?
Correspondence to: A. Yu. Rulev; e-mail: rulev@irioch.irk.ru.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
ꢀC
2013 Wiley Periodicals, Inc.
1

2
Rulev
R2
R2
OH
TABLE 1 Catalyst Screening for the Hydrophosphonylation
of 2-Bromo-3-phenylpropenal 1a with Dimethyl Phosphite 2a
R3ONa / R3OH
R1
R1
P(O)(OR3)2
+ (R3O)2P(O)H
O
Entry
Catalyst
3a Yielda (%)
X
X
3a–f
1a–d
2a,b
1
2
3
4
CaO
KOH
DBU
95
63
82
95
1: R1 = H, R2 = Ph, X = Br (a); R1 = H, R2 = Ph, X = Cl (b);
R1 = H, R2 = Me, X = Cl (c); R1 = R2 = Ph, X = Cl (d)
2: R3 = Me (a); Et (b)
MeONa
a1H NMR yield. Toluene was used as an internal standard for yield
calculation.
3: R1 = H, R2 = Ph, X = Br, R3 = Me (a); R1 = H, R2 = Ph, X = Br, R3 = Et (b);
R1 = H, R2 = Ph, X = Cl, R3 = Et (c); R1 = H, R2 = Me, X = Cl, R3 = Me (d);
R1 = R2 = Ph, X = Cl, R3 = Et (e); R1 = R2 = Ph, X = Cl, R3 = Me (f)
First, the reaction was studied under solvent-free
and catalyst-free conditions. Unfortunately, only sig-
nals of the initial aldehyde 1a and phosphite 2b were
observed in the 1H and 31P NMR spectra after stand-
ing of the reaction mixture at room temperature for
2 days. However, 2 weeks later, the doublet of
CH(OH) moiety at 4.8 ppm (1H NMR) as well as
the resonance signal at 20.6 ppm (31P NMR) of the
target α-hydroxy phosphonate 3b appeared but the
quantity of the adduct was ∼15% only.
SCHEME 1 Addition of dialkyl phosphites to α-haloenals.
TABLE 2 Synthesis of α-Hydroxy phosphonates 3a–f
Entry
1
2
Catalyst
3
Yielda (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1d
2a
2a
2a
2b
2b
2a
2a
2b
MeONa
CaO
DBU
EtONa
EtONa
MeONa
MeONa
EtONa
3a
3a
3a
3b
3c
3d
3e
3f
76
67
60
83
80
89
93
84
In search for the optimal experimental con-
ditions of the preparation of the target hydroxyl
phosphonates 3 the phosphonylation of enal 1a
with dimethyl phosphite 2a was carried out us-
ing both mineral and organic base catalysts
such as calcium oxide, potassium hydroxide, 1,8-
diazabicyclo[54,0]undec-7ene (DBU) and sodium
methoxide.
aIsolated yields.
catalytic amount of a concentrated solution of
sodium methoxide in methanol the hydroxy phos-
phonate 3a was formed smoothly and chemoselec-
tively in high yield (Table 1, entry 4). According to 1H
NMR and 31P NMR spectra of the reaction mixture,
no products of 1,4-addition, halogen substitution, or
polymerization were observed.
Thus, sodium alkoxide as one of the best catalyst
of the reaction was used in a variety of α-haloenals
1a–d. Really, all the target hydroxyl phosphonates 3
were isolated in high yield after column chromatog-
raphy (Scheme 1, Table 2).
To explore the generality of this transforma-
tion, the dependence of the reaction on the struc-
ture of α-haloenals 1 was analyzed. To study the
influence of the halogen atom, the treatment of 2-
chloro-3-phenylpropenal 1b with the diethyl phos-
phite 2b was performed. Like its bromo-bearing ana-
logue, the target phosphonate 3c was isolated only
(Table 2, entry 5). The increase in access to β-olefin
carbon atom did not considerably affect the reac-
tion course. Thus, the changing the phenyl to methyl
group of the initial enal had shown the same reactiv-
ity: The expected hydroxy phosphonate 3d was ob-
tained as the sole product under the same conditions
in high yield (Table 2, entry 6).
In past years, ecofriendly and efficient catalytic
methods for the addition of phosphorus nucle-
ophiles to activated alkenes were reported [17–24].
It was found, for example, that the synthesis of α-
hydroxy phosphonates from the simplest enones or
enals and dialkyl phosphites proceeded successfully
using metal oxides as a promoter [6, 17]. Among
them, the calcium oxide was found to be an effi-
cient catalyst of such type of reactions. In fact, when
the homogeneous mixture of the α-haloenals 1a and
dimethyl phosphite 2a was treated with an equimo-
lar quantity of CaO at slightly elevated temperature
for 0.5 h the result was excellent: The adduct 3a was
obtained in 95% yield (Table 1, entry 1). In con-
trast, potassium hydroxide was less effective: The
target adduct 3a was obtained in moderate yield
only (Table 1, entry 2). When the same reaction
was examined in the presence of DBU (15 mol%),
the adduct yield reached 82% (Table 1, entry 3).
Finally, very good results were obtained when the
phosphonylation of α-haloenals 1a was carried out
in a traditional manner similar to that described
for α,β-unsaturated carbonyl compounds. Thus, the
2-bromo-3-phenylpropenal 1a was treated with an
equimolar quantity of dimethyl phosphite 2a un-
der solventless conditions and in the presence of a
The same procedure can also be successfully ap-
plied to β,β-disubstituted enals. When the optimized
conditions were employed for the addition of dialkyl
Heteroatom Chemistry DOI 10.1002/hc

Hydrophosphonylation of α-Haloalkenals
3
phosphites 2a,b to α-chloro-β,β-diphenyl propenal
1d, the α-hydroxy phosphonates 3e,f were isolated
in excellent yields (Table 2, entries 7, 8).
sequence of the corresponding enals as reported pre-
viously [26].
Next, the influence of experimental conditions
on the reaction course has been examined. Pre-
vious studies have shown that the chemoselectiv-
ity of addition of phosphorus nucleophiles to α,β-
unsaturated carbonyl derivatives is controlled by
the temperature: In general, the heating favors the
phospha-Michael addition [6, 25]. To check this ob-
servation, the enal 1a was reacted with dimethyl
phosphite 2a at 75◦C. In this case, the speed of the
reaction increased and transformation of 1a into 3a
achieved ∼70% in 15 min. However, no reversal in
chemoselectivity occurred: The signals of 1,2-adduct
were only observed in both 1H and 31P NMR spectra.
Typical Procedure for the Synthesis of
α-Hydroxy Phosphonates 3a–f
The concentrated solution of sodium alkoxide (3–5
drops) was added to the mixture of the α-haloenal
1 (1 mmol) and dialkyl phosphate 2 (1 mmol). The
mixture was stirred at room temperature. The re-
action was monitored by TLC. The pure α-hydroxy
phosphonates 3a–f were afforded by column chro-
matography (silica gel, CHCl3:MeOH 95:5 or pure
Et2O). The following α-hydroxy phosphonates 3a–f
have been obtained using this method:
Dimethyl (Z)-2-bromo-1-hydroxy-3-phenyl-2-pro-
penylphosphonate (3a). 1H NMR (CDCl3): δ 3.82
CONCLUSIONS
2
(s, 3H), 3.85 (s, 3H), 4.82 (d, JPH = 13.7 Hz, 1H),
In conclusion, in spite of the fact that the secondary
amino group and halogen atom have the same elec-
tronic effects (+M and –I), the chemical behavior
of α-halo- and aminoenals in the nucleophilic re-
actions is very different. In contrast to captodative
formyl(amino)alkenes, their halogenated analogues
react with dialkyl phosphites to provide exclusively
the α-hydroxy phosphonates in good to excellent
yield. The reaction proceeded smoothly and chemos-
electively and appears tolerant to any changes in
the structure of α-haloenals and experimental con-
ditions.
5.14 (br, s, 1H), 7.25–7.40 (m, 3H), 7.55–7.65 (m,
2H). 13C NMR (CDCl3): δ 54.0 (OCH3), 74.7 (d, J =
165 Hz, CH), 120.1 ( C Br), 128.0, 128.2, 129.0,
130.9, 134.9 (C6H5), 131.0 (CH ). 31P NMR (CDCl3):
δ 22.76. IR: 1231 (P O), 1631 (C C), 3162 (OH). MS
(70 ev): 211 (32), 209 (32), 102 (100). C11H14BrO4P:
calcd. C 41.15, H 4.39, Br 24.88, P 9.65; found C
41.26, H 4.67, Br 25.10, P 9.82.
Diethyl (Z)-2-bromo-1-hydroxy-3-phenyl-2-pro-
penylphosphonate (3b). 1H NMR (CDCl3): δ 1.35–
1.50 (m, 6H), 4.20–4.35 (m, 4H), 4.45 (br s, 1H), 4.81
(d, 2JPH = 13.7 Hz, 1H), 7.25–7.45 (m, 4H), 7.60–7.75
(m, 2H). 13C NMR (CDCl3): δ 16.6 (CH3), 63.8 (dd,
J = 31.0, 7.3 Hz, OCH2), 74.6 (d, J = 163 Hz, CH),
120.6 ( C Br), 128.2, 128.4, 129.2, 131.0, 135.2
(C6H5), 131.1 (CH ). 31P NMR (CDCl3): δ 20.61. IR:
1229 (P O), 1632 (C C), 3283 (OH). MS (70 ev):
211 (64), 209 (64), 102 (100). C13H18BrO4P: calcd. C
44.72, H 5.20, P 8.87; found C 44.47, H 5.43, P 8.53.
EXPERIMENTAL
General Remarks
1H, 13C, and 31P NMR spectra were recorded
on a Bruker AVANCE 400 MHz spectrometer
(Switzerland) at 400.16, 100.61, and 161.97 MHz,
respectively, for the solution in CDCl3 or CD3CN.
Chemical shifts (δ) in ppm are reported using resid-
ual chloroform (7.25 for H and 77.20 for 13C) or
1
acetonitrile (1.94 for 1H and 1.40, 118.60 for 13C) as
an internal reference. The coupling constants (J) are
given in hertz. The IR spectra were recorded with
a Bruker Vertex 70 FT-IR spectrometer and with a
portable Varian 3100 diamond ATR/FT-IR spectrom-
eter. The GC/MS analyses were performed with a
Shimadzu GCMS-QP5050A instrument (Japan) (EI
70 eV). Elemental analysis was carried out with a
Thermo Scientific FLASH 2000 analyzer (Italy). The
silica gel used for flash chromatography was 230–
400 mesh. All reagents were of reagent grade and
were either used as such or distilled prior to use. All
the solvents were dried by standard procedures and
freshly distilled prior to use. α-Haloenals 1a–d were
prepared by the halogenation–dehydrohalogenation
Diethyl (Z)-2-chloro-1-hydroxy-3-phenyl-2-pro-
penylphosphonate (3c). 1H NMR (CDCl3): δ 1.35–
1.45 (m, 6H), 4.25–4.30 (m, 4H), 4.43 (br s, 1H),
2
4
4.73 (d, JPH = 13.3 Hz, 1H), 7.01 (d, JPH = 4.0
Hz, 1H), 7.30–7.45 (m, 3H), 7.65–7.70 (m, 2H). 13C
NMR (CDCl3): δ 16.3 (CH3), 63.5 (dd, J = 31.0, 7.3
Hz, OCH2), 73.1 (d, J = 163 Hz, CH), 127.2, 128.0,
129.2, 134.2 (C6H5), 128.1 (CH ), 128.8 ( C Cl).
31P NMR (CDCl3): δ 20.53. IR: 1238 (P O), 1640
(C C), 3247 (OH). MS (70 ev): 165 (82), 103 (100).
C13H18ClO4P: calcd. C 51.24, H 5.95, Cl 11.63; found
C 51.06, H 6.00, Cl 11.55.
Dimethyl (Z)-2-chloro-1-hydroxy-2-butenylphos-
phonate (3d). 1H NMR (CDCl3):
δ 1.50–1.60
Heteroatom Chemistry DOI 10.1002/hc

4
Rulev
(m, 3H), 3.58 (d, 3JPH = 10.5 Hz, 3H), 3.59 (d, 3JPH
=
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10.5 Hz, 3H), 4.40 (dd, J = 13.2, 6.5 Hz, 1H), 5.45–
5.50 (m, 1H), 5.85–5.95 (m, 1H). 13C NMR (CDCl3):
δ 13.5 (CH3), 53.5 (OCH3), 71.4 (d, J = 168 Hz, CH),
124.6 (d, J = 10 Hz, CH ), 129.7 ( C Cl). 31P NMR
(CDCl3): δ 22.86. IR: 1246 (P O), 1656 (C C), 3309
(OH). MS (70 ev): 214 (M+ + 1), 110 (88), 79 (100).
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Diethyl
2-chloro-1-hydroxy-3,3-diphenyl-2-pro-
penylphosphonate (3e). 1H NMR (CDCl3): δ 1.25–
1.45 (m, 6H), 4.15–4.25 (m, 4H), 4.52 (br s, 1H),
2
5.05 (d, JPH = 14.0 Hz, 1H), 7.20–7.40 (m, 10H).
13C NMR (CDCl3): δ 16.5 (CH3), 63.2 (dd, J = 41.0,
7.0 Hz, OCH2), 69.2 (d, J = 165 Hz, CH), 127.9
( C Cl), 128.1, 128.5, 129.2, 139.6, 140.2 (C6H5),
143.5 (CH ). 31P NMR (CDCl3): δ 20.65. IR: 1238
(P O), 1604 (C C), 3283 (OH). MS (70 ev): 241
(100), 178 (98). C19H22ClO4P: calcd. C 59.93, H
5.82, Cl 9.31, P 8.13; found C 59.82, H 5.92, Cl 9.28,
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Dimethyl 2-chloro-1-hydroxy-3,3-diphenyl-2-pro-
penylphosphonate (3f). 1H NMR (CDCl3): δ 3.78 (d,
3
3JPH = 10.6 Hz, 3H), 3.83 (d, JPH = 10.6 Hz, 3H),
3.89 (br s, 1H), 4.99 (dd, J = 14.5, 5.6 Hz, 1H), 7.25–
7.40 (m, 10H). 13C NMR (CDCl3): δ 53.6 (d, J = 7 Hz,
OCH3), 53.9 (d, J = 7 Hz, OCH3), 69.0 (d, J = 165
Hz, CH), 127.9 ( C Cl), 128.1, 128.6, 129.2, 129.3,
139.6, 140.1 (C6H5), 144.0 (CH ). 31P NMR (CDCl3):
δ 22.70. IR: 1215 (P O), 1616 (C C), 3185 (OH). MS
(70 ev): 241 (76), 178 (100). C17H18ClO4P: calcd. C
57.88, H 5.14, Cl 10.05, P 8.78; found C 57.46, H
5.12, Cl 10.40, P 9.01.
SUPPORTING INFORMATION
Experimental procedures and spectral data with 1H,
13C, and 31P NMR are available as Supporting Infor-
mation from the online issue of the journal.
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Heteroatom Chemistry DOI 10.1002/hc